Molecular targeting and treatment of EGFRvIII-positive gliomas using boronated monoclonal antibody L8A4.

Abstract

PURPOSE:

The purpose of the present study was to evaluate a boronated EGFRvIII-specific monoclonal antibody, L8A4, for boron neutron capture therapy (BNCT) of the receptor-positive rat glioma, F98(npEGFRvIII).

EXPERIMENTAL DESIGN:

A heavily boronated polyamido amine (PAMAM) dendrimer (BD) was chemically linked to L8A4 by two heterobifunctional reagents, N-succinimidyl 3-(2-pyridyldithio)propionate and N-(k-maleimidoundecanoic acid)hydrazide. For in vivo studies, F98 wild-type receptor-negative or EGFRvIII human gene-transfected receptor-positive F98(npEGFRvIII) glioma cells were implanted i.c. into the brains of Fischer rats. Biodistribution studies were initiated 14 days later. Animals received [(125)I]BD-L8A4 by either convection enhanced delivery (CED) or direct i.t. injection and were euthanized 6, 12, 24, or 48 hours later.

RESULTS:

At 6 hours, equivalent amounts of the bioconjugate were detected in receptor-positive and receptor-negative tumors, but by 24 hours the amounts retained by receptor-positive gliomas were 60.1% following CED and 43.7% following i.t. injection compared with 14.6% ID/g by receptor-negative tumors. Boron concentrations in normal brain, blood, liver, kidneys, and spleen all were at nondetectable levels (<0.5 microg/g) at the corresponding times. Based on these favorable biodistribution data, BNCT studies were initiated at the Massachusetts Institute of Technology Research Reactor-II. Rats received BD-L8A4 ( approximately 40 microg (10)B/ approximately 750 mug protein) by CED either alone or in combination with i.v. boronophenylalanine (BPA; 500 mg/kg). BNCT was carried out 24 hours after administration of the bioconjugate and 2.5 hours after i.v. injection of BPA for those animals that received both agents. Rats that received BD-L8A4 by CED in combination with i.v. BPA had a mean +/- SE survival time of 85.5 +/- 15.5 days with 20% long-term survivors (>6 months) and those that received BD-L8A4 alone had a mean +/- SE survival time of 70.4 +/- 11.1 days with 10% long-term survivors compared with 40.1 +/- 2.2 days for i.v. BPA and 30.3 +/- 1.6 and 26.3 +/- 1.1 days for irradiated and untreated controls, respectively.

CONCLUSIONS:

These data convincingly show the therapeutic efficacy of molecular targeting of EGFRvIII using either boronated monoclonal antibody L8A4 alone or in combination with BPA and should provide a platform for the future development of combinations of high and low molecular weight delivery agents for BNCT of brain tumors.

• Authors: Weilian Yang, Rolf F Barth, Gong Wu, Shinji Kawabata, Thomas J Sferra, Achintya K Bandyopadhyaya, Werner Tjarks, Amy K Ferketich, Melvin L Moeschberger, Peter J Binns, Kent J Riley, Jeffrey A Coderre, Michael J Ciesielski, Robert A Fenstermaker, Carol J Wikstrand
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 12 Issue 12 Pg. 3792-802 (Jun 15 2006) ISSN: 1078-0432 [Print] United States
• PMID: 16778107 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antibodies, Monoclonal
• Boron Compounds
• Iodine Radioisotopes
• Recombinant Proteins
• epidermal growth factor receptor VIII
• ErbB Receptors

Topics

• Animals
• Antibodies, Monoclonal (therapeutic use)
• Boron Compounds (therapeutic use)
• Boron Neutron Capture Therapy
• Brain Neoplasms (pathology, radiotherapy)
• ErbB Receptors (analysis, genetics, metabolism)
• Glioma (pathology, radiotherapy)
• Humans
• Injections
• Iodine Radioisotopes (pharmacokinetics, therapeutic use)
• Rats
• Recombinant Proteins (metabolism)
• Transfection